1. The Field of the Invention
The present invention relates to novel compounds showing activity in the central nervous systems (CNS). More specifically, the present invention relates to novel compounds with anticonvulsant activity that exhibit increased/improved toxicological safety (i.e., decreased toxicity), increased/improved metabolic stability, longer half-life, and/or a superior side effect profile, while producing similar or increased biological activity (i.e., efficacy), when compared to currently available CNS therapeutic agents.
2. The Related Technology
A number of pathological conditions (e.g., epilepsy, stroke, bipolar affective disorder, migraine headaches, anxiety, depression, insomnia, schizophrenia, chronic or neuropathic pain, spasticity, spinal cord injury, and chronic neurodegenerative disorders), and diseases (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease) are characterized by abnormalities in the normal function of the central nervous system (CNS). These conditions and diseases typically respond to pharmacologic intervention with compounds or substances that modulate CNS activity. Compounds with this activity include the compounds of the present invention, which are herein disclosed to treat abnormalities of the CNS, such as epilepsy. While currently available therapeutants often have good CNS activity, they frequently exhibit other undesirable properties, such as chronic toxicity, severe and/or unpleasant side effects, and inadequate pharmacokinetic properties, such as a short pharmacologic half-life. For example, a short half-life in a CNS therapeutant may require its frequent administration in order to sustain therapeutic concentrations of the drug without eliciting adverse effects, and where frequent dosing schedules are required, the cost of therapy may increase. In addition, as the required dosing frequency increases, patient compliance tends to decrease. It would therefore be desirable to provide additional compounds that modulate CNS activity and have improved properties, such as, e.g., an increased half-life, increased activity (i.e., improved efficacy), and/or increased metabolic stability (e.g., fewer toxic metabolites) when compared to those of currently available therapies. Furthermore, improved and simpler/simplified synthetic and chemical manufacturing processes can be developed which can help to make the useful compounds of the invention more widely available to a larger portion of the patient population.
Related art may be found in U.S. Pat. No. 5,463,125 (Sandoval et al., “Phenyl alcohol amides having anticonvulsant activity”), WO9941229 [Carvajal Sandoval et al., “Halogenated phenyl alcohol amides (ligands of GABAB receptor) having an anticonvulsant activity”], WO03091201 (Carvajal Sandoval et al., “DL-Hydroxy-alkyl-phenylamides having anticonvulsive activity”), WO2005085182 (Meza Toledo, “DL-Hydroxybenzamides having anticonvulsive activity”), and U.S. Patent Application 20060287397 (Meza Toledo, “Dl-Hydroxy-alkyl-phenylamides having anticonvulsive activity”). An important distinction between the art cited above and that of the present invention is that the cited art contains and refers to compounds which are structurally related to gamma-hydroxybutyric acid (gamma-hydroxybutyrate, or GHB), whereas the compounds of the present invention are structurally related to 3-methylbutyramide.
It is noteworthy that the derivatization (N-alkylation) of the nitrogen atom of amide groups has produced compounds such as N,N-diethylisovaleramide (A. Liebrecht, German Patent 129,967, issued 1902), which has been marketed previously as a sedative (“Valyl”) (see various editions of The Merck Index). However, this compound has been shown instead to exhibit CNS-stimulating, anxiogenic, and convulsant properties (U.S. Pat. No. 5,506,268). Indeed, N-methylated amide derivatives can show either CNS-stimulating or -depressing properties, whereas N-ethyl and larger derivatives generally possess CNS-stimulating properties [Volwiler, E. H. and D. L. Tabern, J. Am. Chem. Soc. (1936) 58:1352-1354; Nelson et al., J. Am. Pharm. Assoc., Sci. Ed. (1941) 30:180-182].
Thus, N,N-disubstituted amide compounds such as cropropamide, crotethamide, ethamivan, nikethamide, N,N-diethylisovaleramide (U.S. Pat. No. 5,506,268), and the insect repellent, DEET (N,N-diethyl-m-toluamide), have all been shown to exhibit CNS-(proconvulsant-) and respiratory-stimulating properties in mammals (including humans). Cropropamide, crotethamide, ethamivan, and niketamide have been used as CNS and respiratory stimulants in humans, e.g., to counteract the potentially life-threatening CNS- and respiratory-depressing effects of barbiturate poisoning (overdose) (various editions of The Merck Index and W. O. Foye's Principles of Medicinal Chemistry).
It is also noteworthy that the primary amide, modafinil (ProVigil) has been shown to possess CNS-stimulant and pro-alertness (pro-vigilance) properties [see the current (14th) edition of The Merck Index]. 